Antibodies have been, and are currently being, developed for the prevention and treatment of various diseases, especially those caused by infectious microorganisms, such as the viruses.
One approach has been the development of antibodies, especially neutralizing monoclonal antibodies, some with high specific neutralizing activity. One drawback to this approach has been the need to produce human antibodies rather than those of mouse or rat and thus minimize the development of human anti-mouse or anti-rat antibody responses, which potentially results in further immune pathology.
An alternative approach has been the production of human-murine chimeric antibodies in which the genes encoding the mouse heavy and light chain variable regions have been coupled to the genes for human heavy and light chain constant regions to produce chimeric, or hybrid, antibodies. For example, a humanized anti-RSV antibody has been prepared and is currently being marketed. [See: Johnson, U.S. Pat. No. 5,824,307]
In some cases, mouse complementarity determining regions (CDRs) have been grafted onto human constant and framework regions with some of the mouse framework amino acids (amino acids in the variable region of the antibody but outside of the CDRs) being substituted for correspondingly positioned amino acids from a human antibody of like specificity to provide a so-called “humanized” antibody [see, for example, Queen, U.S. Pat. Nos. 5,693,761 and 5,693,762]. However, such antibodies contain intact mouse CDR regions and have met with mixed effectiveness and exhibiting affinities often no higher than 107 to 108 M−1.
The production of high potency antibodies (i.e., antibodies with high biological activity, such as antigen neutralizing ability), including antibodies with ultra high affinity for the target antigen, would be desirable from the point of view of both the neutralizing ability of such an antibody as well as from the more practical aspects of requiring less antibody in order to achieve a desirable degree of clinical effectiveness, thereby cutting costs of use.
Antibody affinity is measured by the binding constant of the antibody for a particular antigen, and such binding constant is often calculated by the ratio of the rate constant for antibody-antigen complex formation (referred to as the “kon” value) to the rate constant for dissociation of said complex (the “koff” value). In accordance with the present invention, it has been determined that antibody potency is a function of the kon value, irrespective of specificity. The present invention thus provides a solution to problems of achieving high antibody potency in that the higher the kon value, the higher the potency of the antibody thereby affording high potency antibodies and a method for producing them.